Recent research has focused on how environmental stressors that an individual is exposed to during their lifetime (e.g., poor diet) can lead to changes in the epigenome that increase the risk of disease. Remarkably, their unexposed descendants may inherit this disease risk through yet-to-be determined epigenetic mechanisms. This non-conventional type of inheritance is called transgenerational epigenetic inheritance (TEI) and involves the transmission of ‘information’ over multiple generations via the gametes. Potential epigenetic information that might be inherited from one generation to the next includes DNA methylation, histone modifications, and/or non-coding RNA. Studying TEI in humans is difficult due to confounding factors, such as long generation times, genetic diversity, and the variable environmental conditions in which we live.

The proposed project will explore TEI mechanisms in mice with a mutation in a gene encoding a key enzyme required for folate metabolism (Mtrrgt). Normally, folate metabolism is required for the transmission of methyl groups destined for the methylation of DNA, RNA, and proteins. Disruption of folate metabolism in the Mtrrgt mice leads to global DNA hypomethylation, epigenetic instability associated with changes in gene expression, and the transgenerational inheritance of a wide spectrum of congenital malformations (e.g., neural tube, heart, and placenta defects) for up to at least the F4 generation. This occurs even when generations F1-F4 are wildtype for the Mtrrgt allele and undergo normal folate metabolism. Preliminary data in the Watson lab shows tissue-specific dysregulation of DNA methylation machinery in Mtrrgt/gt mutant mice and wildtype F2 generation mice derived from an Mtrr-deficient grandparent.

We hypothesize that disruption of DNA methylation caused by Mtrr deficiency leads to altered DNA methylation machinery expression and activity in germ and somatic cells that might enable the widespread reconstruction of abnormal DNA methylation patterns in subsequent wildtype generations. The main goal of the proposed project will be to manipulate folate metabolism and the expression of DNA methylation machinery separately and together in cell culture and in mice to determine whether morphological, molecular, and epigenetic phenotypes associated with Mtrr deficiency are exacerbated or rescued. Building from previous work in the lab, particular focus will be on germ cells and trophoblast cells, the latter of which have the greatest epigenetic instability of tissues tested in Mtrrgt mouse line. Together, this data will lead to a greater mechanistic understanding of epigenetic inheritance and also the mechanistic role of folate metabolism during development, the details of which are unclear.

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